As Genetic Testing for Cancer Expands, Questions Still Remain

October 17, 2017

As mutations in more genes are linked to the development of cancer, tests that identify the glitches are growing more expansive — but some gray areas remain.

SUSAN KARNICK was surprised when a genetic test found she had three genetic mutations that might increase her risk of developing breast cancer. — PHOTO BY RENATÉ BIMBI

When a genetic counselor recommended multigene panel testing based on her family history, Susan Karnick didn’t anticipate anything significant in the results.

Relatives on her mother’s side of the family had experienced breast cancers, some at an early age, as well as a number of other cancer types, and their mammograms had often appeared abnormal. Karnick, too, had received abnormal mammogram results, but she had thankfully reached the age of 51 without a cancer diagnosis.

The counselor explained that the test would examine 32 different genes to look for mutations associated with an elevated risk of cancer. Until a few years ago, genetic testing focused on only a few cancer susceptibility genes in a given patient — for instance, BRCA1 and BRCA2 for breast cancer.

“I thought I would probably have some weird variants, but I wasn’t expecting any major results to come up,” says Karnick, a resident of Crystal Lake, Illinois, who took the panel test in March. “So imagine my surprise when I tested positive for abnormal PALB2, ATM and a variant of PTEN which is likely to be pathological.”

All three gene mutations are known to increase breast cancer risk. A healthy PALB2 gene interacts with BRCA2 to repair damaged DNA. A 2014 study of 311 women who had a PALB2 mutation found that their breast cancer risk was 9.47 times higher than average. The ATM gene also helps to repair damaged DNA and stop cell division until this repair is complete, and a metaanalysis of abnormal variants points to a relative breast cancer risk of 2.8 times higher than average. Mutations in PTEN are linked to Cowden syndrome, in which patients have a high risk of both benign and cancerous breast tumors.

The results were extremely unusual, as it’s rare for genetic counselors to find more than one cancer-associated gene mutation in any patient. Karnick, shocked by the results and their seemingly dire outlook, said she felt an immense amount of stress and anxiety. Although grateful for the knowledge, she was confused about what to do next. Similarly, Uduak Andy, M.D., had mixed feelings after receiving her panel test results earlier this year. At just 35, Andy already has had cancer twice. In 2012, she was diagnosed with breast cancer and had a bilateral mastectomy, but tested negative for BRCA1 and BRCA2 mutations.

Only a few years later, shortly after her second daughter was born, doctors found low-grade cancer in Andy’s appendix.

Andy then took a panel test for mutations to 28 genes that can cause cancer susceptibility. Although she felt relief that no major mutations were found, the positive results that did come up were unclear. Two variants of unknown significance (VUS) were identified in the APC and CHEK2 genes. These have yet to be classified by researchers as harmless or pathogenic.

However, it is known that people with APC gene mutations can develop pre-cancerous polyps in their colon and rectum, and abnormal variants of the CHEK2 gene are known to confer moderate risk of breast cancer, with an estimated relative risk of three times greater than average.

“We did all that testing, and nothing was clearly positive. It’s great that nothing major was found, but we don’t really know what these variants of unknown significance mean,” says Andy, who works as a urogynecologist in Philadelphia. “In that respect, the results have been both good and frustrating.”

Sometimes, over time and by tracking large groups of patients who carry an inherited genetic mutation, experts can figure out if a particular VUS is associated with cancer and reclassify it as either pathogenic or benign.

That’s one dynamic that has led to the replacement of smaller, more focused tests with broader panel testing of several genes at once. For individuals who have a strong family history of cancer, like Karnick, or who were diagnosed at a young age, like Andy, panel testing offers a chance to take early action and manage risk with preventive strategies such as surgery. In people who already have cancer, genetic testing can provide clues about which targeted or other drugs might be the most effective treatments.

A major barrier to gathering any of this information is simply low participation. Seventy-five percent of eligible women have never discussed genetic testing with a health care provider, according to a study recently published in the Journal of Clinical Oncology. In many cases, this may be because providers are not up to date about when a patient should be referred for genetic counseling. Another deterrent is a lack of genetic counselors in many regions.

Those who do participate are confronted with some gray areas. The jury is still out on which genes should be included on tests, because, even as some VUSs join the ranks of mutations classified as dangerous or benign, others with less certain effects are are likely to show up.

“If somebody has a BRCA1 mutation, we can tell her that she has a 65 percent lifetime risk of breast cancer.

These numbers for BRCA1 and BRCA2 are really wellknown at this point, and we can give detailed recommendations on what to do next,” said Fergus Couch, Ph.D., the Zbigniew and Anna M. Scheller Professor of Medical Research at the Mayo Clinic. “For the newer genes on these panels, we don’t necessarily have all that information.”

Those kinds of results raise questions about whether a patient is really at risk and in need of enhanced screening or even preventive surgery.

Furthermore, some gene mutations, even if they are known to promote cancer, are not specifically treatable with any targeted drugs.

Although BRCA-driven breast cancers may respond well to a class of drugs known as PARP inhibitors, there may be no specialized treatments for cancers driven by mutations that are not yet targetable.


Genetic testing for breast cancer risk originated with the discovery of the gene BRCA1. In 1990, geneticists at the University of California, Berkeley discovered that the long arm of chromosome 17 contains a segment of DNA that tracks with inherited susceptibility to breast cancer in families with early-onset disease. Then, the race to find a gene and an associated mutation was on. In 1994, University of Utah researchers identified the complete sequence of BRCA1 and confirmed mutations in some high-risk families, marking the discovery of the first gene associated with hereditary breast cancer. A mere two years later, scientists did the same with a second breast cancer susceptibility gene, BRCA2.

Commercial genetic testing for BRCA1 and BRCA2 soon followed. In November 1996, Myriad Genetics, a University of Utah spin-off, began offering a commercial test called BRACAnalysis. In the United States, women with a BRCA1 mutation have a 55 to 65 percent chance of developing breast cancer by age 70, compared with an average lifetime risk of about 12 percent, and those with a BRCA2 mutation have a 45 percent chance.

Myriad Genetics held patents on the genes’ DNA sequences and attempted to sue other companies offering their own BRCA tests. However, in a landmark decision, the Supreme Court ruled in June 2013 that human genes cannot be patented because they are products of nature. Commercial multigene panel tests that included BRCA1 and BRCA2 began appearing more frequently, and at lower costs.

In addition, innovations in sequencing technology and bioinformatics led to the ability to test for multiple genes at the same time. Next-generation sequencing, or NGS, allows millions of DNA fragments to be sequenced in parallel for fast turnaround times and low cost.

So, although breast cancer susceptibility genes other than BRCA1 and BRCA2 were previously identified — for instance, the association with CHEK2 has been known since 2002 — they weren’t commonly included in tests until more recently. A 2015 study in the New England Journal of Medicine reported that today’s panel tests cover mutations to more than 100 genes, with 21 of those associated with breast cancer risk.

But just because technology can sequence dozens of genes at once, does that mean it automatically should? Experts warn patients to think carefully about the pros and cons of getting several genes tested before diving in. Aside from BRCA1 and BRCA2, high-risk genes typically include PALB2, PTEN, CDH1 and TP53. Gene mutations known to confer moderate risk are those in CHEK2, NF1 and ATM. Limited information exists for more recently discovered genes, such as BARD1, BRIP1, FANCC, NBN, RAD51C, RAD51D and XRCC2. Some of these genes are associated with certain other cancer types, too. For instance, PTEN can contribute to the development of colorectal or endometrial cancers, melanoma and others, and TP53 can be associated with all of those, plus ovarian, pancreatic, gastric and prostate cancers.

Even less is known about other genes that panels can include. The NEJM study found that STK11, CDH1 and NBN variants have an established link to breast cancer, but risk estimates remain too imprecise to categorize as high, moderate or low. It also concludes that risks attributed to PTEN, STK11 and CDH1 variants may be overestimated.

“If you test for BRCA1 and BRCA2 only, you miss about 40 percent of the predisposing mutations for breast cancer — but there are caveats to that,” says Couch, who also coauthored the study. “The major issue is that there are genes on these panels that we don’t actually know with certainty drive breast cancer. It may be that, as we move forward, some of these panels will shrink.”

In other cases, gene mutations are clearly associated with a variety of cancers — for example, TP53 mutations are thought to drive more than half of all cancers — but no drugs exist yet that target them.

Testing for such genes might not give doctors information they can act on, but it can open the door to clinical trials, or to drugs that will be approved in time.


Despite the caveats, many physicians and patients believe the advantages of panel testing outweigh the possible disadvantages. The main benefit is having the knowledge to take on measures to lower or manage one’s cancer risk.

For BRCA1 or BRCA2 mutations, women can choose to get more intensive breast cancer screening, take risk-reducing medications such as tamoxifen or raloxifene, which block the body’s production of estrogen, or have preventive surgery to remove both breasts and/or ovaries. The National Comprehensive Cancer Network has established guidelines for managing risks due to other some other gene mutations: increased breast screening and possible risk-reducing mastectomy in those with mutations to the ATM or CDH1 genes, and consideration of preventively removing the ovaries and fallopian tubes at ages 45 to 50 for those with BRIP1 mutations.

For women who have breast cancer, being aware of the presence of some of these mutations may help determine which chemotherapies and/or targeted drugs are likely to be the most effective.

Another advantage of panel testing is being able to alert other family members, such as children or siblings, to their possible cancer risk. Testing might be recommended for them, as well, if the results show a mutation.

Many of these mutations also drive more than one type of cancer, which could expand screenings to other areas of the body. For instance, Karnick will now get a colonoscopy every three years and an abdominal MRI with contrast every six months, because her mutations predispose her to gastrointestinal cancers in addition to breast cancer. Also, she will be screened for breast cancer every six months, alternating between MRI and ultrasound exams. She ultimately plans to have a bilateral mastectomy.

Because physicians simply don’t have enough information regarding certain aspects of panel testing, patients often must make decisions based on their own preferences and judgment.

“If you only want information consistent with your family history, you could limit the number of genes on your panel test. Or you could be someone that can deal with uncertainty, and so you can choose to do a big panel,” says Susan Domchek, executive director of the Basser Center for BRCA and the Basser Professor in Oncology at the University of Pennsylvania.

As in Andy’s case, a large number of genes on the panel means a greater probability of detecting a VUS. For BRCA1 and BRCA2, the VUS rates are down to about 2 percent, says Domchek, but a 40-gene panel could end up with 20 to 30 percent of people getting a confusing result.

In addition, VUS rates are known to be higher among ethnic minorities due to lower testing volume and less data available about genetic variants among diverse populations.

Part of Andy’s frustration over her results came from the fact that her genetic variant, seen in individuals of African ancestry more than 50 percent of the time, remains inconclusive. As a black woman, she hopes her results add to the pool of available data on African-American women to help future generations better assess their cancer risk.

Despite the initial stress, Karnick has no regrets about taking a panel test. Finding out about her mutations not only pushed her to take preventive measures, but also motivated her to finally attend graduate school for social work. She also volunteers as a peer navigator for Facing Our Risk of Cancer Empowered, a nonprofit organization devoted to supporting those predisposed to hereditary cancers. There, she mentors people with mutations similar to her own.

“I really believe knowledge is power,” says Karnick, who also underwent genetic testing for the sake of her three children. She wants to be with them for as long as possible, and she wants them to be fully informed when they make their own health care decisions someday. In that spirit, she has donated blood to be used to study these mutations, and hopes that this will help her children and others in the future.

“Overall, I’m really happy I have this knowledge and, moving forward, I can be as proactive as possible,” she says. “I’m grateful for that.”